SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 15 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 16

PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 16 DETAILED PHARMACOLOGY 20 TOXICOLOGY 23 REFERENCES 27

PART III: CONSUMER INFORMATION 31

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Known hypersensitivity to salmon calcitonin (s-calcitonin) or to any component of the formulation (See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

WARNINGS AND PRECAUTIONS

Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists. There have been rare reports of serious allergic-type reactions, such as bronchospasm, swelling of the tongue or throat, tachycardia, hypotension, collapse and anaphylactic shock in post marketing. The usual provisions should be made for the emergency treatment of such a reaction should it occur. Allergic reactions should be differentiated from generalized flushing and hypotension. Skin testing should be considered prior to treatment with MIACALCIN * NS for patients with suspected sensitivities to calcitonin. (see Monitoring and Laboratory Tests section)

Nasal adverse events occurred in 17% of patients who received MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray and in 14% of patients who received placebo nasal spray in studies in postmenopausal females. Therefore, a nasal examination should be performed prior to start of treatment with nasal calcitonin and at any time nasal complaints occur. In all postmenopausal patients treated with MIACALCIN * Nasal Spray, the most commonly reported nasal adverse events included rhinitis (8.2%), nasal dryness (3.9%), epistaxis (2.4%), and sinusitis (1.6%). In clinical trials in another disorder (Paget's Disease), 2.8% of patients developed nasal ulcerations. If severe ulceration of the nasal mucosa occurs, as indicated by ulcers greater than 1.5 mm in diameter or penetrating below the mucosa, or those associated with heavy bleeding, MIACALCIN Nasal Spray should be discontinued. Although smaller ulcers often heal without withdrawal of MIACALCIN *Nasal Spray, medication should be discontinued temporarily until healing occurs.

There are no adequate and well controlled studies in pregnant women with s- calcitonin. MIACALCIN * NS is not indicated in pregnancy.

Synthetic calcitonin (salmon) has been shown to cause a decrease in fetal birth weights without any fetal abnormalities in rabbits when given by injection in doses 70-278 times the intranasal dose recommended for human use based on body surface area . Since synthetic calcitonin (salmon) does not cross the placental barrier, this may be due to metabolic effects in the pregnant animal.

It is not known whether this drug is excreted in human milk and should not be administered to nursing mothers.

Synthetic calcitonin (salmon) has been shown to inhibit lactation in animals and should not be administered to nursing mothers.

The safety and efficacy of MIACALCIN * in children have not been established. Its use is not recommended in pediatrics.

: Clinical trials using MIACALCIN * NS have included postmenopausal women up to 77 years of age. No unusual adverse events or increased incidence of common adverse events have been noted in patients over 65 years of age.

Skin testing should be considered prior to treatment with MIACALCIN * NS for patients with suspected sensitivities to calcitonin. The following procedure is suggested: Prepare a dilution of 10 IU per mL by withdrawing 0.05 mL of commercially available synthetic calcitonin (salmon) solution for injection in a tuberculin syringe and filling it to 1.0 mL with Dextrose Injection 5%, USP (or Saline Injection, USP). Mix well, discard 0.9 mL and inject intracutaneously 0.1 mL (approximately 1 IU) on the inner aspect of the forearm. Observe the injection site 15 minutes after injection. The appearance of more than mild erythema or wheal constitutes a positive response.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most commonly reported adverse events with MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray were local effects such as rhinitis, nasal dryness with crusting, non-severe epistaxis and sinusitis. In normal adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin results in only a slight decrease in serum calcium. When bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray has been evaluated for safety in more than 650 patients treated for osteoporosis for up to two years. Table 1 is based on controlled trials in patients treated with MIACALCIN * NS at doses of 50, 100, 200, or 400 IU/day for up to 2 years. The table includes all AEs with an incidence of 1% or greater in the MIACALCIN * NS all combined doses treatment group, irrespective of causal relationship to study drug. In approximately one-half of the patients tested after six months or more of treatment, indications of circulating antibodies to salmon calcitonin were obtained. In most patients the presence of antibodies does not reduce the clinical efficacy of exogenous salmon calcitonin.

Table 1: Common AEs occurring in >= 1% of patients receiving MIACALCIN *NS, combined doses treatment group for up to 2 years, by body system (regardless of study drug relationship)

Body system/ Adverse Event	MIACALCIN * NS (n=697) %	Placebo (n=389) %
Respiratory thoracic and mediastinal disorders
Rhinitis	8.2	5.4
Nasal dryness	3.9	3.6
Epistaxis	2.4	2.1
Nasal Crusting	2.2	2.8
Nasal discomfort	1.6	1.0
Sinusitis	1.6	0.5
Upper Respiratoty Tract Infection	1.4	2.3
Nasal Irritation Pharingitis	1.4 1.0	1.5 1.0
Gastro-intestinal disorders	3.0	1.5
Abdominal pain	3.0	1.5
Constipation	1.7	1.8
Nausea	1.7	1.0
Dyspepsia	1.6	0.3
General disorders	1.6	2.6
Influenza symptoms	1.6	2.6
Fatigue	1.1	0.3
Vascular disorders	1.7	0.8
Hypertension	1.7	0.8
Flushing	4.6	5.1
Nervous system disorders	2.7	2.8
Headache	2.7	2.8
Depression	1.6	1.5
Dizziness	1.6	0.8
Musculoskeletal and connective	2.9	0.8
tissue disorders
Back pain
Arthralgia	2.0	1.8
Bone fracture	1.4	1.5
Arthrosis	1.0	1.0
Eye Disorders Lacrimation abnormal	1.0	0.8
Infections and infestations	1.1	1.0
Cystitis	1.1	1.0
Infection	1.4	1.0

MIACALCIN * has also been evaluated for safety in more than 900 patients, who were at least 1- year postmenopausal, treated for up to 5 years in the Prevent Recurrence of Osteoporotic Fractures (P.R.O.O.F.) Trial. Similar types of adverse reactions were reported in this study. However, the incidence for adverse reactions in this trial, involving 942 patients exposed to MIACALCIN * Nasal Spray and 307 patients exposed to placebo nasal spray, were generally higher than in the 2 year trials due to the longer observation period. In addition, these events were reported with a similar frequency in both the MIACALCIN * and placebo groups. Table 2 includes P.R.O.O.F AEs occuring in >= 1% of patients receiving MIACALCIN *NS, assessed as definitely, probably, possibly, or unlikely drug related by the investigators.

Table 2: P.R.O.O.F: AEs occurring in >= 1% of patients receiving MIACALCIN *NS, regardless of study drug relationship

Body system/ Adverse Event	MIACALCIN * NS (n= 942) %	Placebo (n=307) %
General disorders and administration site conditions Edema (e.g. tongue, extremity, face, generalized) Accidental trauma * Asethenia * Chest pain * Hot flushes *	3.1 1.0 1.3 2.9 1.3	2.6 1.3 1.0 2.9 2.0
Cardiovascular disorders Arrhythmia *	1.0	1.6
Gastrointestinal disorders Diarrhea,	1.8	1.0
Dysgeusia	1.3	1.0
Hearing and Vestibular disorder Ear Disorder * (eg sensation of fullness, stuffiness, blockage)	1.0	1.3
Immune system disorders Allergy	1.6	1.4
Metabolic and Nutritional disorders Hypercalcemia *	1.7	1.3
Muscoluskeletal disorders	5.5	5.9
Arthropathy *	5.5	5.9
Leg pain *	2.2	2.3
Pain * (eg musculoskeletal, general)	4.5	5.5
Nervous system disorders Headache Dysphonia * Somnolence *	3.9	7.2
Respiratory, thoracic and	30.6	20.8
mediastinal disorders
Rhinitis (including nasal edema,
nasal congestion, sneezing, allergic
rhinitis)
Nasal discomfort (e.g. nasal odour,	15.8	13.0
nasal mucosal erythema, mucosal
excoriation).
Epistaxis	12.6	11.7
Rhinitis ulcerative	3.4	1.6
Abnormal Chest Sounds * (eg	1.2	1.0
basilar, crepitations, rales)
Skin Disorders
Skin disorder * (eg fissures,leisions,	1.6	0.7
sores)
Dry skin *	1.1	0.3
Vascular Disorder Purpura	1.3	0.7
Vision disorders	2.8	1.3
Cataract *	2.8	1.3
Eye abnormality * (dryness,	1.2	2
infection, irritation)
Glaucoma *	1.0	0.0

*additional adverse reactions that occurred in the P.R.O.O.F. trial not included in the 2 years trial data.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Gastrointestinal disorders:

Nausea, vomiting. These effects usually subsided spontaneously.

General disorders and administration site conditions:

Dizziness, flushing accompanied by a sensation of heat and chills. These effects usually subsided spontaneously.

Genito-urinary disorders:

Uncommonly polyuria. These effects usually subsided spontaneously.

Immune system disorders:

MIACALCIN * Nasal Spray may give rise to hypersensitivity reactions such as generalized skin reactions, flushing, edema (facial, extremity and generalized), hypertension and arthralgia. Allergic and anaphylactoid-like reactions and single case of anaphylactic shock have been reported.

Respiratory, thoracic and mediastinal disorders:

Nasal polyp, nasal septum ulceration, and nasoseptal deviation. Most of the nasal events were mild to moderate in severity and did not prompt discontinuation. MIACALCIN * Nasal Spray nasal adverse event rates were 73.5% mild, 24.3% moderate, and 2.2% severe (placebo nasal spray adverse event rates were 69.5% mild, 24.3% moderate, and 6.2% severe).

Abnormal Hematologic and Clinical Chemistry Findings

Antibodies to salmon calcitonin In approximately one-half of the patients tested after six months or more of treatment, indications of circulating antibodies to salmon calcitonin were obtained. In most patients the presence of antibodies does not reduce the clinical efficacy of exogenous salmon calcitonin. Urine sediment abnormalities Urine sediment abnormalities have not been reported in ambulatory volunteers treated with MIACALCIN * Nasal Spray. Coarse granular casts containing renal tubular epithelial cells were reported in the urine of young adult volunteers at bed rest who were given injectable synthetic calcitonin (salmon) in order to determine the effect of MIACALCIN * on immobilization osteoporosis. There was no other evidence of renal abnormality and the urine sediment became normal after salmon calcitonin therapy was stopped.

Post-Market Adverse Drug Reactions

Rash generalised, pruritis, cough, isolated anaphylactic-type reactions and anaphylactoid reactions including tachycardia, hypotension and collapse. Single case of anaphylactic shock have been reported.

DRUG INTERACTIONS

Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium concentrations. The dose of lithium may need to be adjusted. Formal studies designed to evaluate drug interactions with s-calcitonin have not been conducted.

The interaction of MIACALCIN *NS with herbal medications or supplements has not been studied.

Effect on ability to drive and use machines: No studies exist on the effects of MIACALCIN *NS on ability to drive and use machines. MIACALCIN * NS may cause fatigue, dizziness and visual disturbances, which may impair the patient's reactions. Patients must therefore be warned that these effects may occur, in which case they should not drive or use machines.

DOSAGE AND ADMINISTRATION

The safety and efficacy of MIACALCIN * in children have not been established. Use is therefore not recommended.

: Clinical trials using MIACALCIN *NS have included postmenopausal women up to 77 years of age.

The recommended dose of MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray in postmenopausal women is one spray (200 IU i.e 0.2 mcg) per day administered intranasally, alternating nostrils daily. Drug effect may be monitored by periodic measurements of lumbar vertebral bone mass to document stabilization of bone mass or increases in bone density.

Patients who miss one dose of MIACALCIN * NS (salmon calcitonin) should not increase the dose of MIACLACIN * NS to compensate for the missed dose or doses, but should continue with therapy as soon as possible.

Instructions on priming of the pump upon first use of the device and nasal introduction of MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray should be given to the patient. Instructions for patients are supplied with individual bottles. Patients should be asked to notify their physician if they develop significant nasal irritation. Patients should be advised of the following:

Nausea, vomiting, flushing and dizziness are known to be dose dependent when MIACALCIN * is administered parenterally. Such events might therefore also be expected to occur in association with an overdose of MIACALCIN *NS. Treatment would be symptomatic. Isolated cases of overdose have been reported but no serious adverse reactions have been associated with high doses. Single doses of MIACALCIN * Nasal Spray up to 1600 I.U. and doses up to 800 I.U. per day for three days and chronic administration of doses up to 600 I.U. per day have been studied without serious adverse effects. A dose of 1000 I.U. of MIACALCIN * (synthetic calcitonin; salmon) injectable solution given subcutaneously may produce nausea and vomiting. A dose of MIACALCIN * injectable solution of 32 I.U. per kg per day for one or two days demonstrated no additional adverse effects. There have been no reports of hypocalcemic tetany. However, the pharmacologic actions of MIACALCIN * Nasal Spray suggest that this could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.

ACTION AND CLINICAL PHARMACOLOGY

Salmon calcitonin (s-Calcitonin) is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. It is of physiological importance in the regulation of calcium metabolism in certain animal species and may also have physiological importance in certain extraskeletal systems (e.g., GI and renal function). MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray (NS) markedly reduces the removal of calcium from bone in conditions with an increased rate of bone resorption such as osteoporosis. Osteoclast activity is inhibited, and osteoblast formation and activity seem to be stimulated. MIACALCIN * NS inhibits bone resorption, thus lowering abnormally increased serum calcium. Additionally, at the beginning of treatment it increases the urinary excretion of calcium, phosphorus, and sodium by reducing their tubular re-uptake. Serum calcium, however, is not reduced below the normal range. Salmon calcitonin acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. Salmon calcitonin appears to have actions essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action. The actions of calcitonin on bone and its role in normal human bone physiology are still incompletely understood. Single injections of synthetic calcitonin (salmon) result in a marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is a persistent, smaller decrease in the rate of bone resorption. Histologically this is associated with a decreased number of osteoclasts and an apparent reduction in their resorptive activity. Decreased osteocytic resorption may also be involved. Because of its chemical nature (a peptide of 32 amino acids), calcitonin may be administered parenterally to achieve maximal absorption. Small percentages of the dose are apparently absorbed when administered by the buccal, oral, topical or inhalation routes; thus far, only the nasal absorption has been well substantiated and demonstrated to show a significant clinical effect.

All calcitonin structures consist of 32 amino acids in a single chain, with a ring of seven amino- acid residues at the N-terminus, the sequence of which differs from species to species. MIACALCIN * (Synthetic Calcitonin; Salmon) Nasal Spray is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. Due to the greater affinity of salmon calcitonin to receptor binding sites than calcitonins from mammalian species, including the synthetic human calcitonin, MIACALCIN * NS is more potent and longer acting. In terms of bioactivity, the potency of MIACALCIN * NS was found to be about half that of the drug given by i.m. or s.c. injection. Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue architecture leading to enhanced bone fragility and consequent increase in fracture risk. The most common type of osteoporosis occurs in postmenopausal females. Osteoporosis is a result of a disproportionate rate of bone resorption compared to bone formation which disrupts the structural integrity of bone, rendering it more susceptible to fracture. The most common sites of these fractures are the vertebrae, hip, and distal forearm (Colles' fractures). Vertebral fractures occur with the highest frequency and are associated with back pain, spinal deformity and a loss of height. The primary action of calcitonin is on bone. Studies have shown that calcitonin most consistently affects the osteoclasts. These cells show decreased function, altered morphology and decreased numbers under the influence of calcitonin. Osteocytic osteolysis also appears to be depressed by this hormone. These effects result in the inhibition by calcitonin of bone resorption. Calcitonin may also stimulate osteoblastic bone formation, but decreases in osteoblastic function have also been reported and final conclusions are not yet possible.

The data on bioavailability of MIACALCIN * NS obtained by various investigators using different methods show great variability, with a range varying between approximately 3 and 50% relative to intramuscular administration. As is the case with other polypeptide hormones, plasma levels of s- calcitonin are not predictive of the therapeutic response, and hence s-calcitonin activity should be evaluated by biochemical or clinical parameters. MIACALCIN * is absorbed rapidly by the nasal mucosa. Maximum plasma concentrations occur within the first hour of administration (median about 10 minutes).

The absolute bioavailability of synthetic calcitonin (salmon) is about 70% after either intramuscular or subcutaneous injection.

In the dose range 100-400 IU, area under the plasma concentration curve (AUC) increases roughly in proportion to the dose. However, administration of doses higher than 400 IU does not result in further increases in the AUC for the drug.

The apparent volume of distribution is 0.15 - 0.3 L/kg, and protein binding amounts to 30-40%.

The patterns of tissue distribution of the hormone seem to differ for the three source species studied thus far and correlate with sites of degradation. Thus, porcine calcitonin tends to accumulate in the liver and kidney and both tissues degrade this form. Human calcitonin shows similar properties except that the kidney is relatively more important for the metabolism of human calcitonin than for porcine calcitonin. In the case of salmon calcitonin, accumulation and degradation seem to occur almost exclusively in the kidney.

In the case of salmon calcitonin, accumulation and degradation seem to occur almost exclusively in the kidney. Degradation of all forms of calcitonin occurs by splitting the molecule into smaller fragments which are biologically and immunologically inactive. Very little renal excretion of the intact calcitonin molecule takes place. It appears that salmon calcitonin cannot cross the placental barrier.

For MIACALCIN NS, the half-life of elimination of synthetic calcitonin (salmon) is calculated to be around 20 minutes. There is no accumulation of the drug on repeated admnistration at 10- hour intervals for up to 15 days. After either intramuscular or subcutaneous injection the elimination half-life is 70 to 90 minutes . Synthetic calcitonin (salmon) and its metabolites are excreted up to 95% by the kidney, the fraction of the parent drug being 2%.

Geriatrics: Clinical trials using MIACALCIN * NS have included postmenopausal women up to 77 years of age. No unusual adverse events or increased incidence of common adverse events have been noted in patients over 65 years of age.

STORAGE AND STABILITY

Unopened MIACALCIN * Nasal Spray should be stored in the refrigerator between 2 and 8degC and protected from freezing. After priming, MIACALCIN * Nasal Spray should be stored at room temperature (between 15- 30degC ) and used within 4 weeks. To ensure correct delivery, the bottle should be kept in an upright position.

SPECIAL HANDLING INSTRUCTIONS

To ensure correct delivery, the bottle should be kept in an upright position. Upon, first use only, the pump must be primed. The product should be allowed to reach room temperature before priming. Pull up the protective cap, holding the bottle in an upright position, press down the upper part until it clicks. Repeat twice. After the first time the dose counter window shows white and red lines, after the second time white, and after the third time green. It is now ready for use. After priming and first use, the product should be stored at room temperature in an upright position. Each bottle contains at least 14 doses.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MIACALCIN * (synthetic calcitonin; salmon) Nasal Spray is available in spray bottles delivering at least 14 metered doses of 200 International Units (IU), one unit corresponding to about 0.2 mcg of synthetic calcitonin (salmon). MIACALCIN * NS spray bottles also contains the following nonmedicial ingredient: benzalkonium chloride, hydrochloric acid, sodium chloride and purified water. Each pack contains 2 bottles of spray solution. The device is composed of a clear, uncoloured glass bottle (glass type I) and a spray mechanism containing an integrated, automatic dose- counting mechanism and a built-in mechanical stop.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Nasal spray	200 IU/actuation	Benzalkonium chloride, hydrochloric acid, sodium chloride and purified water. For a complete listing see Dosage Forms, Composition and Packaging section.

Control # 113496

Date of Revision:

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3